Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the curative potential of chemo-radiation, one third of patients relapse and many develop devastating treatment-induced morbidities. Thus, new targets for treatment are urgently needed. We recently discovered that placental growth factor (PlGF) is highly expressed in the MB-cancer cels and MB-associated stromal cells. Furthermore, our preliminary data suggest that secretion of sonic hedgehog (Shh) by MB cells induces stromal PlGF expression in a paracrine manner. Finally, we found that PlGF blockade significantly inhibits MB growth and spread to the spinal cord in orthotopic human xenografts of MB. Building on these exciting preliminary findings, we now propose to unravel the mechanisms of response to anti-PlGF therapy in multiple subtypes of MBs using genetically engineered mouse models (GEMM), human MB cell lines and state-of-the-art imaging. Our long- term goal is to translate these findings to the clinic to treat MB. In Aim 1, we will dissect the mechanism o regulation of PlGF expression in MB by the Shh pathway, a major driver of tumorigenesis in MB. In Aim 2, by analyzing the PlGF signal transduction axis in MB cells, we will determine how PlGF governs MB cell survival and growth. Lastly, in Aim 3 we will determine whether anti-PlGF therapy leads to improved tumor control and mouse survival in GEMMs and orthotopic models of genetically defined MBs. To realize these aims, we have developed powerful, non-invasive, high-resolution imaging technologies that provide unprecedented molecular, cellular, structural and functional insight (Nature Medicine 2001, 2003, 2004, 2009) and reveal various steps of tumor progression (Nature Reviews Cancer 202; Nature Methods 209, 2010). We will use these techniques and the unique collective expertise of our multi-disciplinary team to uncover the role of PlGF pathway in MB using GEMMs, available through our collaborators. Similar to our findings on VEGF blockade in other solid tumors, our findings on PlGF-blockade will inform future clinical trials in MB (Nature Medicine 2004; New England Journal of Medicine 2009). PUBLIC HEALTH RELEVANCE: The current treatment options for medulloblastoma-the most prevalent form of pediatric brain cancer-cause devastating morbidities and result in tumor relapse in a significant fraction of patients. By revealing its mechanism of action, the proposed study aims to demonstrate PlGF as a novel therapeutic target for medulloblastoma. Our findings will directly inform the design and help interpret the results of potential clinical trials of antiPlGF therapy in medulloblastoma patients.